PROJECT SUMMARY/ ABSTRACT Dr. Majithia's goal is to elucidate mechanisms of disease and identify therapeutic targets for Type 2 Diabetes (T2D). To achieve this long-term goal, this proposal details a comprehensive five-year training program for mentored career development in molecular endocrinology to enable his transition as an independent investigator. Dr. Majithia has completed clinical training in endocrinology, diabetes and metabolism at the Massachusetts General Hospital. To develop an independent research program focused on elucidating molecular mechanisms for T2D, he proposes a course of didactic and hands-on research training to mature an investigative approach combining human genetics, cell-based experimentation, and clinical phenotypes. To this end, the he has established a joint mentorship between David Altshuler, a pioneer in human genetics and genome interpretation at the MGH/Broad Institute, and Evan Rosen, an internationally recognized adipocyte biologist at Harvard Medical School. Additionally, he has assembled a diverse and international scientific advisory committee consisting of Harvey Lodish, Krishna Chatterjee, and Henry Kronenberg, luminary scientists in the fields of insulin resistance, nuclear hormone receptor mutations in humans, and molecular endocrinology. Together, these mentors and advisors with diverse fields of expertise in genetics, cell-based science and clinical phenotyping form an ideal team to foster Dr. Majithia's own multi-disciplinary approach. The proposed research aims to 1) apply a novel, experimentally based method to interpret the function of all possible mutations in PPARG, an important drug target for T2D treatment; 2) quantify the relationship between PPARG mutations, protein function, and T2D risk; 3) demonstrate general applicability of these methods beyond PPARG. To accomplish these aims, Dr. Majithia will leverage a unique resource available through his mentor's laboratory-sequenced genomes and clinical data on thousands of individuals. The research aims of this proposal will enable Dr. Majithia to advance skills in genome scale data analysis, develop novel, high- throughput experimental methods of general interest, and demonstrate application of these methods to the interpretation of human sequencing data. Collectively, the experience gained from the proposed experiments and structured career development plan will serve as a strong foundation for the Dr. Majithia's R01 proposal and his transition to an independent clinician-investigator.